Rate of onset of drug effect (a function of both rate of administration and rate of binding to active site) is believed, on the basis of animal studies and clinical experience, to be an important influence on the reinforcing effects of drugs of abuse, but this has never been systematically studied in humans with stimulant drugs. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. One component of this project is systematically evaluating the influence of dose and infusion rate on the effects of IV cocaine, in order to establish whether a slower rate of administration reduces cocaine effects. In animals, low calorie diets increase drug self-administration. A recently completed residential study reproduced this phenomenon in human drug users, using nicotine (cigarette smoking) as the target drug. These findings have clinical implications, especially since some drugs of abuse themselves suppress appetite and thus may produce calorie deprivation. A recently begun outpatient study will evaluate the relationship between calorie deprivation produced by intentional dieting and cigarette smoking in patients attempting smoking cessation. The primary enzyme metabolizing cocaine in humans is butyrylcholinesterase (BChE). Alterations in BChE activity might alter cocaine levels and thus alter cocaine's effects, with possible therapeutic benefits. A collaborative study with the Preclinical Pharmacology Laboratory and the National Institute on Aging is evaluating the influence of altered BChE activity on the acute effects of cocaine in monkeys.